This is a continuation of a collaborative effort to elucidate molecular mechanisms associated with three types of chemically- induced neurotoxic syndromes that resemble naturally-occurring neurological disorders: I, the induction of neurofilament (NF) accumulations in peripheral axons by gamma-diketones and IDPN; II, the toxic action of lathyrogens and related aminonitriles; and III, MPTP-induced Parkinsonism. In Part A of Project I, trifluoromethyl-substituted analogs of 2,5- hexanedione (2.5-HD) will be synthesized, compared to the parent compound in chemical model studies, and evaluated for neurotoxicity in rats, in an effort to address how gamma-diketone-induced pyrrole formation at NF-based lysine epsilon-amino groups leads to NF accumulations. Also NMR studies are described which may allow direct visualization of the nature of chemical modification of NF. Part B will focus on elucidating the toxic activation pathways responsible for both the morphological and behavioral neurotoxic. effects of beta, beta'-iminodipropionitrile (IDPN). This will involve the synthesis and biological evaluation of analogs and suspected metabolites, as well, as both chemical model and in vitro metabolism experiments. In Project II, a proposed mechanism for the irreversible inactivation of lysyl oxidase by beta- aminopropionitrile (BAPN), based on chemical modification of the covalently-bound cofactor pyrroloquino-line quinone (PQQ, methoxatin), will be tested in chemical model studies, and correlated with enzymatic activities of BAPN analogs. A related mechanism proposed to explain the neurolathyrogenic properties of beta-cyanoalanine will be studied, and may, lead to a new strategy for the design of suicide inactivators for pyridoxal enzymes, particularly amino acid decarboxylases. Project III is directed at clarifying the structural basis of cytotoxicity of l-methyl-4- phenylpyridinium (MPP+), the neurotoxic metabolite of the selective dopaminergic (DA) neurotoxin l-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). Experiments are proposed to confirm that MPP+ neurotoxicity is a consequence of its passive accumulation inside mitochondria in response to the transmembrane potential, where it inhibits Complex I of the respiratory chain, causing a toxic depletion of ATP. This inhibitory activity of MPP+ analogs will be correlated with (i) their DA neurotoxicity upon intranigral infusion in rats and (ii) their selective uptake into DA neurons.